Relapse to habitual drug use is a characteristic feature of cocaine addiction and perhaps the most difficult to treat. Accumulating evidence suggests that relapse is linked to drug craving and can be triggered by cocaine-associated stimuli (cues) and acute re-exposure to the drug itself (priming). Development of preclinical models that simulate relevant features of cocaine use and relapse patterns in people is crucial for evaluating the impact of these triggers and for developing effective strategies to combat addiction. Our proposed research will adapt i.v. self- administration techniques in nonhuman primates to provide a new model with which to investigate environmental and pharmacological variables contributing to the reinstatement of extinguished cocaine-seeking behavior and to evaluate potential pharmacological strategies for relapse prevention. In the experiments we propose, monkeys will be provided with extended histories of cocaine self-administration under conditions in which persistent drug-seeking is maintained jointly by cocaine injections and by presentations of a cocaine-paired stimulus (second-order schedule). Cocaine-seeking behavior subsequently will be extinguished for periods of time ranging up to months by substituting vehicle for cocaine and omitting presentations of the stimulus. Using this model, we will determine the capacity of the cocaine-paired stimulus and of cocaine priming injections, individually and in combination, and to reinstate extinguished cocaine-seeking behavior. We also will track the time course and persistence of reinstatement and determine its pharmacological specificity with selected licit and illicit drugs that exhibit profiles of action overlapping that of cocaine. An important issue that can be addressed using our proposed model is the extend to which medications intended for use as pharmacological substitutes for cocaine might themselves induce relapse. Consequently, we will investigate candidate drugs of this type for their liability to mimic the priming effects of cocaine. Finally, we will evaluate potential anti-relapse medications for their capacity to block reinstatement of cocaine-seeking behavior without producing nonselective behavior disruptions and for the degree to which such drugs retain long-term effectiveness. Overall, the proposed research will provide relevant information for evaluating pharmacological and environmental determinants of relapse and its treatment.